The .alpha.-aminopenicillins, such as for example ampicillin, amoxicillin and cyclacillin, are very useful antibiotics which are widely used against a large number of gram-positive and gram-negative micro-organisms.
These semisynthetic penicillins have been prepared by various processes and there is a large body of literature dealing with these methods of preparation. A number of patent applications and patents disclose preparations in which 6-aminopenicillanic acid is acylated with mixed anhydrides derived from the modified Dane salts of D-2-amino-(substituted)-acetic acid. Such methods of preparation are described in Netherlands Pat. No. 142,4l6; British Pat. No. 1,347,979 and U.S. Pat. Nos. 3,316,247, 3,325,479 and 4,123,611.
The Dane salts described in the literature can be either of the ester-type or the amide-type, i.e. in Dane salts having the general formula: ##STR3## wherein ##STR4## represents an amino acid residue and M is hydrogen or an alkali metal, and when Z is an alkoxy group they are of the ester-type, while when Z is an amino or substituted amino group they are of the amide-type.
The ester-type Dane salts have been widely used in preparing .alpha.-aminopenicillins and one process employing these salts is described in U.S. Pat. No. 4,128,547. In the general Dane salt/6-aminopenicillanic acid acylation process, the N-protected aminopenicillin which is formed during the acylation step is hydrolyzed to yield the desired .alpha.-aminopenicillin and, in the case of ester-type Dane salts, a .beta.-ketoester. These .beta.-ketoesters are generally liquids which are separated from the water-soluble .alpha.-aminopenicillin salts by extraction in an organic solvent. However, this is a significant disadvantage of the ester-type Dane salts since the .beta.-ketoesters are not readily recovered from solution and so recycle of these .beta.-ketoesters for the preparation of further starting Dane salts is not practicable on a commercial scale.
The amide-type Dane salts, in which Z is an amino or substituted amino group, are not as well-known as the ester-types and have not received as much attention in the literature. The amide-type Dane salts in which Z is the group NR.sub.1 R.sub.2 --, wherein R.sub.1 is hydrogen and R.sub.2 is o- or p-methoxyphenyl have been described in Chem. Ber., 98, 789 (1965) and Belgian Pat. No. 824,158. Those in which R.sub.1 is hydrogen and R.sub.2 is phenyl or halophenyl have been described in Swiss Pat. No. 476,758 and British Pat. No. 1,339,605. Those in which R.sub.1 and R.sub.2 are both alkyl or NR.sub.1 R.sub.2 are morpholino have been described in Netherlands Pat. No. 142,416, British Pat. No. 1,339,605 and U.S. Pat. No. 4,123,611. Those in which R.sub.1 and R.sub.2 are both aryl or in NR.sub.1 R.sub.2 form a piperidino ring have been described in U.S. Pat. No. 4,123,611. These known amide-type Dane salts, however, have the disadvantage that they generally give poor yields of the final product .alpha.-aminopenicillins.
The prior art also shows that it is advantageous to protect the carboxylic acid group or both the amino and carboxylic acid groups of 6-aminopenicillanic acid before it is reacted with the desired Dane salt. The proposed useful protecting groups include the trialkylhalosilanes, as in British Pat. No. 1,339,605 and U.S. Pat. No. 4,128,547; dialkyldihalosilanes, as in U.S. Pat. No. 3,654,266; and silanes having at least one C--O--Si bond in the molecule, such as in U.S. Pat. No. 3,868,364. However, the protection of the carboxylic group or carboxylic and amino groups of 6-aminopenicillanic acid has not produced an improvement in the overall prior art processes' economics, since their other disadvantages, such as low yield, complexity of procedure and low-purity of final product are not overcome thereby.